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Query: UMLS:C0598934 (tumor growth)
 58,965 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Tumor growth decreases T-cell recognition of self major histocompatibility complex (MHC) class II molecules by inducing changes in splenic macrophage (M phi) phenotype and function. The current investigation shows tumor-induced alterations in autorecognition also are associated with changes in responsiveness to and production of granulocyte-M phi colony-stimulating factor (GM-CSF). In contrast to normal host (NH) M phi, tumor-bearing host (TBH) M phi failed to express higher MHC class II molecule density after exposure to GM-CSF. Autoreactive T cells stimulated by either NH or TBH M phi were suppressed by GM-CSF. Inhibition of prostaglandin E2 (PGE2) synthesis reversed M-CSF-induced suppression of autoreactivity to NH M phi and, to a lesser extent, to TBH M phi. When TBH autoreactive T cells were stimulated by TBH M phi, autoreactivity increased when GM-CSF was added and PGE2 synthesis was inhibited. Although GM-CSF can contribute to tumor-induced suppression, it did not affect the contribution of GM-CSF during autorecognition. Increased GM-CSF production was responsible, at least in part, for the TBH M phi-mediated suppression. Low concentrations of GM-CSF were produced endogenously by tumor isolates, and GM-CSF production was significantly increased when isolates were stimulated with lipopolysaccharide. Autoreactive T cells stimulated solely by TBH M phi produced more GM-CSF than autoreactive T cells stimulated by NH M phi. Cultures supplemented with several concentrations of NH or TBH M phi produced similar amounts of GM-CSF in a dose-dependent manner. Inhibition of PGE2 synthesis by NH and TBH M phi reduced GM-CSF production equally. Collectively, these results suggest that during tumor growth, responsiveness to and production of GM-CSF alters recognition of self MHC class II molecules.
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PMID:Tumor growth changes responsiveness to and production of granulocyte-macrophage colony-stimulating factor during recognition of self MHC class II molecules. 129 76

Xenopus laevis lymphoid tumor cells of the ff genotype grow after transplantation in inbred ff tadpoles or young post-metamorphic animals, but do not grow in fully grown ff adults. The ability to grow is lost progressively after metamorphosis and is apparently due to an immune response of the adult host against minor histocompatibility antigens (non-MHC encoded) expressed by the tumor cells. The difference in alloimmune responses between the larval and the adult immune system of the amphibian Xenopus has been subsequently investigated with this new in vivo model. The resistance of the host against transplanted tumor cells rises during the post-metamorphic development in parallel with the second histogenesis observed in the thymus, the expression of MHC class II by peripheral T cells and the recovery of T cell effector functions such as MLR, and can be abrogated by sub-lethal irradiation. Pre-immunization of ff adults with irradiated ff-2 cells specifically accelerates subsequent ff skin graft rejection, which implies the generation of memory against antigenic determinants common between the ff skin and the tumor cells. Similarly, both anti-ff alloserum and anti-ff-2 serum contain antibodies specifically precipitating two surface proteins (180-200 kDa) from ff-2 cells. One of these proteins is also detected on normal ff thymocytes and splenic T cells. On the other hands, ff-2 tumor cells (MHC I+II-) are not rejected by class I-negative tadpoles (class I expression on the tumor cell surface is even increased), and no anti-tumor antibody response can be detected. However, tumor growth has been reduced in tadpoles following priming with irradiated ff-2 cells, although immunization is not sufficient to prevent ultimate tumor development and tadpole death. Moreover, priming with irradiated ff-2 cells at larval stages does interfere with tumor growth in transplanted young post-metamorphic adults, suggesting that long-lived memory has been generated and has been maintained through metamorphosis. These results suggest that the lack of tumor rejection by larvae results from an incomplete effector function rather than an absence of recognition. Full responsiveness against minor H antigens cannot be elicited before adulthood.
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PMID:Ontogeny of the alloimmune response against a transplanted tumor in Xenopus laevis. 758 97

The coexistence of tumor-specific immunity with a progressing tumor is observed in most experimental systems and remains one of the major paradoxes of tumor immunology. Expression of several surface molecules on melanoma cells, e.g., intercellular adhesion molecule 1 (ICAM-1) or major histocompatibility complex (MHC) class II, has been associated with an aggressive tumor growth and an reduced host antitumor response. HLA class I expression is also frequently altered in melanoma compared to melanocytes. Given the central role of these molecules in the restriction of T cell recognition, regulation of tumor HLA class I expression might also be a strategy for the evasion of immune surveillance by the malignant cells. The fact that it is now possible to clone antigen-specific T cells from tumor patients, as well as the relevant autologous tumor cell lines, enabled us to establish a model system to investigate possible tumor escape mechanisms from immunosurveillance. Using this system, we were able to demonstrate that purified soluble ICAM-1 or 12-fold-concentrated cell-free melanoma supernatants, containing shed ICAM-1, were able to inhibit conjugate formation between T cell clones and the autologous melanoma cells as efficiently as monoclonal antibodies against CD11a, Soluble ICAM-1 also abrogated the MHC-restricted killing of the melanoma by T cell clones. We further observed that a number of CD4+ T cell clones and melanoma cell lines established from the same tumors form conjugates with each other, leading to an increase of [Ca2+]i in the T cell clone; however, this interaction failed to induce interleukin-2 production or proliferation of the T cell clone. Furthermore, this interaction rendered the T cell clone unresponsive to subsequent stimulation. All these effects were MHC class II restricted. Therefore, the melanoma was capable of delivering antigen-specific signals to the T cell clone, but did not deliver the costimulatory signals, e.g., a B7/CD28 interaction, necessary for full T cell activation. Transfection of the melanoma with an expression vector containing a B7 cDNA with subsequent B7 expression on its cell surface renders the melanoma a fully competent antigen-presenting cell which is able to induce a nuclear factor binding to the interleukin-2 promoter in the specific T cell clone, followed by enhanced interleukin-2 transcription, synthesis, and T cell proliferation.
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PMID:Lymphocyte-melanoma interaction: role of surface molecules. 759 91

Apoptosis is a major cause of cell death in health and disease. In contrast to necrosis, apoptosis does not induce an inflammatory response and the cellular debris produced by apoptosis has been assumed to be biologically inert. This review challenges this assumption by suggesting that apoptotic debris (especially in the context of growing tumors or during HIV infection) may have immunological activities, mainly immunosuppressive but perhaps also immunostimulatory. In many cases, the surface of apoptotic cells differs from normal cells in that phosphatidylserine (PS) is aberrantly exposed on the external face of the cell membrane. Liposomes composed of PS may down-modulate macrophage anti-leishmanial activities, suppress macrophage TNF production, suppress lymphocyte proliferation, and increase macrophage proliferation. "Membrane shedding" has been described in certain malignancies where apoptosis may be occurring, and the shed tumor membrane vesicles have been shown to reduce MHC class II expression on macrophages and decrease lymphocyte responsiveness, perhaps because of their ganglioside content. Finally, the apoptotic debris from HIV-infected cells may bear on its surface viral proteins which contain immunosuppressive peptide sequences. This debris may also use viral envelope proteins to fuse into macrophages and thereby avoid phagocytosis and lysosomal destruction. These considerations suggest that the flux of apoptosing cells and debris through the immune system that occurs during tumor growth and HIV infection should not be assumed to be immunologically neutral. In particular, HIV-related apoptosis may have immunosuppressive effects in addition to the numerical depletion of lymphocytes.
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PMID:The immunological potential of apoptotic debris produced by tumor cells and during HIV infection. 773 82

CD4+ autoreactive T cells are a major cell population in regulating immune responses to altered autologous neoplastic cells. Normal autoreactive T cells recognize major histocompatibility complex (MHC) class II molecules in association with self-peptides on antigen-presenting cells, such as macrophages (M phi). Tumor-bearing hosts (TBH) have decreased autoreactivity partly because tumors increase M phi secretion of suppressor molecules like prostaglandin E2 (PGE2) and decrease M phi MHC class II expression. Because interleukin (IL)-10, a cytokine produced by T cells, M phi, and tumor cells, inhibits production of most M phi suppressor molecules, we determined if IL-10 could reverse tumor-induced murine splenic M phi-mediated suppression of autoreactive T cell proliferation. Tumor growth enhanced activated M phi production of PGE2, nitric oxide, and tumor necrosis factor-alpha (TNF-alpha). IL-10 strongly reduced or inhibited M phi production of these molecules. When added to pure normal host (NH) CD4+ T cells, NH syngeneic splenic M phi stimulated autoreactive T cell proliferation more than did TBH splenic M phi. Exogenous IL-10 or M phi preincubation with IL-10 restored TBH M phi-stimulated autoreactivity to normal levels. IL-10 treatment had little or no effect on NH M phi-stimulated autoreactivity. IL-10 inhibited TBH M phi secretion of suppressor molecules in T cell proliferation assays because supernatants from IL-10-pretreated TBH M phi-syngeneic NH T cell cultures had decreased levels of suppressor molecules. When endogenous IL-10 activity was neutralized with anti-IL-10 monoclonal antibody, autoreactive T cell proliferation stimulated by NH or TBH M phi was slightly, but significantly decreased. Although IL-10 is known to inhibit M phi foreign antigen-presenting cell-dependent T cell proliferation, this study shows that IL-10 restores autoreactive T cell functions during tumor growth by counteracting M phi production of inhibitory molecules. These data suggest that IL-10 up-regulates anti-cancer autoreactive T cell responses by down-regulating suppressor M phi activity.
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PMID:Promotion of macrophage-stimulated autoreactive T cell proliferation by interleukin-10: counteraction of macrophage suppressor activity during tumor growth. 778 92

In crescentic glomerulonephritis, crescent formation involves the active participation of glomerular epithelial cells (GEC) and macrophages recruited to the glomerulus during the evolution of the disease. Cytokines derived from macrophages may affect many functions of GEC. In this study, we found that interleukin-1 beta (IL-1 beta) inhibited GEC growth (DNA synthesis and cell number) in vitro in a dose- and time-dependent manner. This effect was not mediated by tumor growth factor beta (TGF beta) which is a potent inhibitor of GEC growth in vitro. Treatment of GEC with various concentrations of IL-1 beta induced morphologic changes consisting in the loss of their cobblestone shape and acquisition of a fibroblast-like appearance. Moreover, IL-1 beta was shown to stimulate the expression of interleukin-6 (IL-6) by GEC. The increase in IL-6 secretion by GEC treated with IL-1 beta was observed at both the protein and mRNA levels. IL-1 beta also affected the metabolism of laminin in cultured GEC, inducing a dose-dependent increase in laminin production in culture supernatants harvested from GEC. Finally, we investigated the expression of MHC class II antigens and intercellular adhesion molecule-1 (ICAM-1) in GEC, and found that unstimulated GEC are negative for MHC class II antigens, as detected by flow cytometry. In contrast to the induction of effector functions, expression of MHC class II antigens stringently required interferon-gamma. IL-1 beta did not induce MHC class I antigen expression. The regulation of ICAM-1 expression in that unstimulated GEC expressed ICAM-1, and this expression was upregulated by IL-1 beta. We conclude that IL-1 beta alters many functions of GEC, and these changes may be involved in the initiation and amplification of glomerular injury.
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PMID:Interleukin-1-beta activation of cultured glomerular epithelial cells. 792 73

The bacterial superantigen staphylococcal enterotoxin A (SEA) is an extremely potent activator of T lymphocytes when presented on major histocompatibility complex (MHC) class II molecules. To develop a tumor-specific superantigen for cancer therapy, we have made a recombinant fusion protein of SEA and the Fab region of the C215 monoclonal antibody specific for human colon carcinoma cells. SEA as part of a fusion protein showed a > 10-fold reduction in MHC class II binding compared to native SEA, and accordingly, the affinity of the FabC215-SEA fusion protein for the C215 tumor antigen was approximately 100-fold stronger than to MHC class II molecules. The FabC215-SEA fusion protein efficiently targeted T cells to lyse C215+ MHC class II- human colon carcinoma cells, which demonstrates functional substitution of the MHC class II-dependent presentation of SEA with tumor specificity. Treatment of mice carrying B16 melanoma cells expressing a transfected C215 antigen resulted in 85-99% inhibition of tumor growth and allowed long-term survival of animals. The therapeutic effect was dependent on antigen-specific targeting of the FabC215-SEA fusion protein, since native SEA and an antigen-irrelevant FabC242-SEA fusion protein did not influence tumor growth. The results suggest that Fab-SEA fusion proteins convey superantigenicity on tumor cells, which evokes T cells to suppress tumor growth.
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PMID:Monoclonal antibody-superantigen fusion proteins: tumor-specific agents for T-cell-based tumor therapy. 809 Jul 50

Tumor-induced changes in macrophage (M phi)2 accessory activities significantly suppress T-cell recognition of allogeneic and syngeneic major histocompatibility complex (MHC) class II molecules. Because these changes are often associated with altered responses to stimulatory and inhibitory cytokines, we investigated the possibility that tumor growth alters the contribution of a macrophage regulatory cytokine, macrophage colony-stimulating factor (M-CSF), during reactivity against allogeneic and syngeneic MHC class II molecules. T-cell reactivity against allogeneic MHC class II molecules was significantly suppressed by tumor-bearing host (TBH) M phi in the presence of M-CSF. M-CSF-induced suppression was independent of TBH M phi prostaglandin E2 (PGE2) synthesis. T-cell reactivity against syngeneic MHC class II molecules increased in the presence of M-CSF when normal host (NH) M phi served as the source of syngeneic molecules. However, T-cell reactivity against syngeneic MHC class II molecules in the presence of M-CSF did not change when TBH M phi served as stimulator/accessory cells. Although T-cell reactivity against NH syngeneic MHC class II molecules was additively increased by M-CSF and indomethacin (a PGE2 synthesis inhibitor) treatment, reactivity against TBH syngeneic MHC class II molecules increased solely through PGE2 synthesis inhibition. Admixtures of both NH and TBH M phi in the absence or presence of M-CSF suggest that tumor-induced suppression was not strictly due to decreased expression of MHC class II molecules. Collectively, these data suggest that TBH M phi are partly suppressive through altered responsiveness to M-CSF.
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PMID:Tumor growth alters macrophage responsiveness to macrophage colony-stimulating factor during reactivity against allogeneic and syngeneic MHC class II molecules. 826 68

Presentation of antigenic peptides by MHC class II molecules to CD4+ T cells is critical to the generation of antitumor immunity. In an attempt to enhance MHC class II antigen processing, we linked the sorting signals of the lysosome-associated membrane protein (LAMP-1) to the cytoplasmic/nuclear human papilloma virus (HPV-16) E7 antigen, creating a chimera (Sig/E7/LAMP-1). Previously, we found that expression of this chimera in vitro and in vivo with a recombinant vaccinia vector targeted E7 to endosomal and lysosomal compartments and enhanced MHC class II presentation to CD4+ T cells compared to vaccinia expressing wild-type E7. In the current study, we tested these recombinant vaccinia for in vivo protection against an E7+ tumor, TC-1, which was derived from primary epithelial cells of C57BL/6 mice cotransformed with HPV-16 E6 and E7 and c-Ha-ras oncogenes. All mice vaccinated with 1 x 10(7) plaque-forming units of wild-type E7-vaccinia showed progressive tumor growth when challenged with a tumorigenic dose of TC-1 tumor cells; in contrast, 80% of mice vaccinated with the chimeric Sig/E7/LAMP1 vaccinia remained tumor free 3 months after tumor injection. Furthermore, treatment with the Sig/E7/LAMP-1 vaccinia vaccine cured mice with small established TC-1 tumors, whereas the wild-type E7-vaccinia showed no effect on this established tumor burden. These findings point out the therapeutic limitations of recombinant vaccinia expressing unmodified tumor antigens. Further, they demonstrate that modifications that reroute a cytosolic tumor antigen to the endosomal/lysosomal compartment can profoundly improve the in vivo therapeutic potency of recombinant vaccines.
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PMID:Treatment of established tumors with a novel vaccine that enhances major histocompatibility class II presentation of tumor antigen. 854 65

The present study was performed to investigate processes involved in circumvention of the immune system by advanced stages of tumor growth in the liver. The efficacy of Kupffer cells and pit cells against cancer cells was tested in vivo in an experimental model of colon carcinoma metastasis in rat liver. Liver tumors were induced by administration of CC531 colon cancer cells into the vena portae. After 3 weeks, livers were obtained and partly fixed for electron microscopic procedures or frozen in liquid nitrogen for enzyme and immunohistochemistry at the light microscope level. The activation status of Kupffer cells was studied by expression of Ia-antigen (MHC class II) and by measurement of glucose-6-phosphate dehydrogenase (G6PDH) activity in the cells in situ as a measure of production of reactive oxygen species. Large numbers of Kupffer cells were found in liver parenchyma surrounding colon carcinomas when compared with levels in control livers, but these cells were not activated. Large numbers of activated monocytes and macrophages, cytotoxic T cells but only a few pit cells were found to be recruited to the boundary between liver parenchyma and tumors or their stroma. In those areas where cancer cells invaded liver parenchyma, only newly recruited macrophages and some Kupffer cells were present but few cytotoxic T cells or pit cells were found. The low activation status of Kupffer cells both in terms of production of reactive oxygen species and Ia-antigen expression and the absence of significant numbers of pit cells at tumor sites suggest that Kupffer cells and pit cells do not play a significant role in advanced stages of tumor growth. High levels of prostaglandin E2 were detected in the parenchyma of livers containing tumors and transforming growth factor beta was detected in the stroma of the tumors, therefore suggest that cytotoxicity of newly recruited monocytes, macrophages and cytotoxic T cells may be limited in these stages because of local production of these immunosuppressive factors.
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PMID:Kupffer cells and pit cells are not effective in the defense against experimentally induced colon carcinoma metastasis in rat liver. 887 11


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